This Mentored Patient-Oriented Research Career Development Award (K23) application seeks to combine a program of focused research, individualized mentorship and didactics to provide the candidate with training in clinical trial design and methodology. The candidate's objective for this application is to pursue a clinical neuroscience approach to systematically delineating biomarkers of placebo effects in depression using novel paradigms and neuroimaging protocols. The resulting biomarkers will be translated into a clinical trial setting and used to develop future novel neuroimaging-informed clinical trial designs. Over the past decade, neuroimaging tools have rapidly advanced the field of neural biomarkers of placebo analgesia. Surprisingly, little progress has been made to investigate the neurobiology of placebo effects in depression, a disease with remarkably and increasingly high placebo rates (Walsh et al., 2002). Furthermore, despite obvious scientific progress in this field, our ability to objectively assess placebo effects in clinical trial setting is lacking. As a consequence, the increased number of failed trials has made large pharmaceutical companies to reduced or discontinued research on medications for brain disorders. In order to objectively asses the neural bases of placebo effects in depression, the candidate has developed a Simulated Real-time Neurofeedback fMRI task, specifically designed to record and modulate mood improvement by providing simulated neurofeedback in the context of intravenous placebo administration with expectations of fast-acting antidepressant effects. In a pilot study, simulated positive neurofeedback was associated with significant acute mood improvement and increased blood oxygen level dependent (BOLD) responses in the rostral anterior cingulate cortex (rACC), a common neural target of placebo and antidepressant treatments. The central hypothesis of this application is that placebo effects in depression are mediated by increased neural activity in the rACC (AIM1), which can be used in clinical trials of antidepressant treatment to predict placebo effects (AIM 2) and assess the effect of antidepressant treatment on placebo-induced rACC neural responses (AIM 3). The candidate's mentors and consultant are experts on clinical trial design and methodology (primary mentor: Dr. Frederic Blow), neuroimaging predictors of placebo effects (co-mentor: Dr. Jon-Kar Zubieta) and neuroimaging biomarkers of antidepressant response in depression (consultant: Dr. Leanne Williams). The results obtained in this application are expected to have an important impact on our ability to detect drug- placebo differences in clinical trial settings. Upon completion of this proposal the candidate will be able to incorporate neuroimaging-based biomarkers into the design, conduct, analysis, and reporting of clinical trial data, in preparation for an R01 submission. The setting for these research and training activities is the Department of Psychiatry at the University of Michigan, a world-renowned center of mental health research and education. The Department of Psychiatry benefits from close collaborative relationships with other units including Radiology, Bioengineering, Psychology, and the Michigan Institute for Clinical and Health Research. This vigorous research environment includes ample access to fMRI facilities and clinical samples, and it nurtures an expanding group of translational psychiatric researchers.